We are comparing the prophylactic therapeutic effects of lithium and carbamazepine in a double-blind, randomized, crossover design, followed by a period of treatment with both drugs in combination in outpatients with manic-depressive illness. Each drug phase lasts up to one year. We are exploring the possible differential clinical efficacy of lithium, carbamazepine, and the combination, and possible clinical and biological correlates of response. We have added a fourth (one year) phase to the study consisting of sodium valproate in combination with lithium. We now have entered 54 patients (53 of whom have been randomized). Patients will have a variety of tests including: hematological, endocrine, lumbar puncture, EEG and MRI studies, as well as an extensive battery of neuro- psychological tests including assessment of psychosensory symptoms. Patients will also have a detailed life chart of their course of illness. A number of self and observer-ratings are performed. Forty-four patients have completed the first drug phase and 31 patients have also completed the second drug phase. In those initially randomized to lithium, 16 of 22 patients were able to complete the year and 6 of 22 patients failed; one patient had to stop because of severe acne. With carbamazepine, 10 of 22 patients were able to complete the year and 12 of 22 patients failed; 6 patients had to stop because they developed a rash. A total of 47 patients have been administered carbamazepine and 9 (19%) have had to stop because of a drug rash. Sixteen patients have entered the fourth arm of the study, consisting of valproate in combination with lithium; several of these are responding extremely well.